Methylene-bridged selective androgen receptor modulators and methods of use thereof

ABSTRACT

This invention provides a class of androgen receptor targeting agents (ARTA). The agents define a new subclass of compounds, which are selective androgen receptor modulators (SARM). Several of the SARM compounds have been found to have an unexpected androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. Other SARM compounds have been found to have an unexpected antiandrogenic activity of a nonsteroidal ligand for the androgen receptor. The SARM compounds, either alone or as a composition, are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of acute and/or chronic muscular wasting conditions; e) preventing and/or treating dry eye conditions; f) oral androgen replacement therapy; g) decreasing the incidence of, halting or causing a regression of prostate cancer; and/or h) inducing apoptosis in a cancer cell.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional Application of U.S. patent applicationSer. No. 10/683,157, filed Oct. 14, 2003, which claims the benefit ofU.S. Provisional Application Ser. No. 60/418,166, filed Oct. 15, 2002,which are incorporated in their entirety by reference herein.

GOVERNMENT INTEREST STATEMENT

This invention was made in whole or in part with government supportunder grant number R29 CA068096 awarded by the National CancerInstitute, National Institute of Health, and under grant numberR15HD35329, awarded by the National Institute of Child Health and HumanDevelopment, National Institute of Health. The government may havecertain rights in the invention.

FIELD OF INVENTION

The present invention relates to a novel class of androgen receptortargeting agents (ARTA), which are selective androgen receptormodulators (SARM). The SARM compounds are useful for a) malecontraception; b) treatment of a variety of hormone-related conditions,for example conditions associated with Androgen Decline in Aging Male(ADAM), such as fatigue, depression, decreased libido, sexualdysfunction, erectile dysfunction, hypogonadism, osteoporosis, hairloss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benignprostate hyperplasia, alterations in mood and cognition and prostatecancer; c) treatment of conditions associated with Androgen Decline inFemale (ADIF), such as sexual dysfunction, decreased sexual libido,hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations incognition and mood, depression, anemia, hair loss, obesity,endometriosis, breast cancer, uterine cancer and ovarian cancer; d)treatment and/or prevention of acute and/or chronic muscular wastingconditions; e) preventing and/or treating dry eye conditions; f) oralandrogen replacement therapy; g) decreasing the incidence of, halting orcausing a regression of prostate cancer; and/or h) inducing apoptosis ina cancer cell.

BACKGROUND OF THE INVENTION

The androgen receptor (“AR”) is a ligand-activated transcriptionalregulatory protein that mediates induction of male sexual developmentand function through its activity with endogenous androgens. Androgensare generally known as the male sex hormones. The androgenic hormonesare steroids which are produced in the body by the testes and the cortexof the adrenal gland or can be synthesized in the laboratory. Androgenicsteroids play an important role in many physiologic processes, includingthe development and maintenance of male sexual characteristics such asmuscle and bone mass, prostate growth, spermatogenesis, and the malehair pattern (Matsumoto, Endocrinol. Met. Clin. N. Am. 23:857-75(1994)). The endogenous steroidal androgens include testosterone anddihydrotestosterone (“DHT”). Testosterone is the principal steroidsecreted by the testes and is the primary circulating androgen found inthe plasma of males. Testosterone is converted to DHT by the enzyme 5alpha-reductase in many peripheral tissues. DHT is thus thought to serveas the intracellular mediator for most androgen actions (Zhou, et al.,Molec. Endocrinol. 9:208-18 (1995)). Other steroidal androgens includeesters of testosterone, such as the cypionate, propionate,phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, anddecanoate esters, and other synthetic androgens such as7-Methyl-Nortestosterone (“MENT”) and its acetate ester (Sundaram etal., “7 Alpha-Methyl-Nortestosterone(MENT): The Optimal Androgen ForMale Contraception,” Ann. Med., 25:199-205 (1993) (“Sundaram”)). Becausethe AR is involved in male sexual development and function, the AR is alikely target for effecting male contraception or other forms of hormonereplacement therapy.

Worldwide population growth and social awareness of family planning havestimulated a great deal of research in contraception. Contraception is adifficult subject under any circumstance. It is fraught with culturaland social stigma, religious implications, and, most certainly,significant health concerns. This situation is only exacerbated when thesubject focuses on male contraception. Despite the availability ofsuitable contraceptive devices, historically, society has looked towomen to be responsible for contraceptive decisions and theirconsequences. Although concern over sexually transmitted diseases hasmade men more aware of the need to develop safe and responsible sexualhabits, women still often bear the brunt of contraceptive choice. Womenhave a number of choices, from temporary mechanical devices such assponges and diaphragms to temporary chemical devices such asspermicides. Women also have at their disposal more permanent options,such as physical devices including IUDs and cervical caps as well asmore permanent chemical treatments such as birth control pills andsubcutaneous implants. However, to date, the only options available formen include the use of condoms and vasectomy. Condom use, however is notfavored by many men because of the reduced sexual sensitivity, theinterruption in sexual spontaneity, and the significant possibility ofpregnancy caused by breakage or misuse. Vasectomies are also notfavored. If more convenient methods of birth control were available tomen, particularly long-term methods which require no preparativeactivity immediately prior to a sexual act, such methods couldsignificantly increase the likelihood that men would take moreresponsibility for contraception.

Administration of the male sex steroids (e.g., testosterone and itsderivatives) has shown particular promise in this regard due to thecombined gonadotropin-suppressing and androgen-substituting propertiesof these compounds (Steinberger et al., “Effect of ChronicAdministration of Testosterone Enanthate on Sperm Production and PlasmaTestosterone, Follicle Stimulating Hormone, and Luteinizing HormoneLevels: A Preliminary Evaluation of a Possible Male Contraceptive,Fertility and Sterility 28:1320-28 (1977)). Chronic administration ofhigh doses of testosterone completely abolishes sperm production(azoospermia) or reduces it to a very low level (oligospermia). Thedegree of spermatogenic suppression necessary to produce infertility isnot precisely known. However, a recent report by the World HealthOrganization showed that weekly intramuscular injections of testosteroneenanthate result in azoospermia or severe oligospermia (i.e., less than3 million sperm per ml) and infertility in 98% of men receiving therapy(World Health Organization Task Force on Methods And Regulation of MaleFertility, “Contraceptive Efficacy of Testosterone-Induced Azoospermiaand Oligospermia in Normal Men,” Fertility and Sterility 65:821-29(1996)).

A variety of testosterone esters have been developed which are moreslowly absorbed after intramuscular injection and thus result in greaterandrogenic effect. Testosterone enanthate is the most widely used ofthese esters. While testosterone enanthate has been valuable in terms ofestablishing the feasibility of hormonal agents for male contraception,it has several drawbacks, including the need for weekly injections andthe presence of supraphysiologic peak levels of testosterone immediatelyfollowing intramuscular injection (Wu, “Effects of TestosteroneEnanthate in Normal Men: Experience From a Multicenter ContraceptiveEfficacy Study,” Fertility and Sterility 65:626-36 (1996)).

Steroidal ligands which bind the AR and act as androgens (e.g.testosterone enanthate) or as antiandrogens (e.g. cyproterone acetate)have been known for many years and are used clinically (Wu 1988).Although nonsteroidal antiandrogens are in clinical use forhormone-dependent prostate cancer, nonsteroidal androgens have not beenreported. For this reason, research on male contraceptives has focusedsolely on steroidal compounds.

Prostate cancer is one of the most frequently occurring cancers amongmen in the United States, with hundreds of thousands of new casesdiagnosed each year. Unfortunately, over sixty percent of newlydiagnosed cases of prostate cancer are found to be pathologicallyadvanced, with no cure and a dismal prognosis. One approach to thisproblem is to find prostate cancer earlier through screening programsand thereby reduce the number of advanced prostate cancer patients.Another strategy, however, is to develop drugs to prevent prostatecancer. One third of all men over 50 years of age have a latent form ofprostate cancer that may be activated into the life-threatening clinicalprostate cancer form. The frequency of latent prostatic tumors has beenshown to increase substantially with each decade of life from the 50s(5.3-14%) to the 90s (40-80%). The number of people with latent prostatecancer is the same across all cultures, ethnic groups, and races, yetthe frequency of clinically aggressive cancer is markedly different.This suggests that environmental factors may play a role in activatinglatent prostate cancer. Thus, the development of treatment andpreventative strategies against prostate cancer may have the greatestoverall impact both medically and economically against prostate cancer.

Osteoporosis is a systemic skeletal diseaseor CHaracterized by low bonemass and deterioration of bone tissue, with a consequent increase inbone fragility and susceptibility to fracture. In the U.S., thecondition affects more than 25 million people and causes more than 1.3million fractures each year, including 500,000 spine, 250,000 hip and240,000 wrist fractures annually. Hip fractures are the most seriousconsequence of osteoporosis, with 5-20% of patients dying within oneyear, and over 50% of survivors being incapacitated. The elderly are atgreatest risk of osteoporosis, and the problem is therefore predicted toincrease significantly with the aging of the population. Worldwidefracture incidence is forecasted to increase three-fold over the next 60years, and one study estimated that there will be 4.5 million hipfractures worldwide in 2050.

Women are at greater risk of osteoporosis than men. Women experience asharp acceleration of bone loss during the five years followingmenopause. Other factors that increase the risk include smoking, alcoholabuse, a sedentary lifestyle and low calcium intake. However,osteoporosis also occurs frequently in males. It is well establishedthat the bone mineral density of males decrease with age. Decreasedamounts of bone mineral content and density correlates with decreasedbone strength, and predisposes to fracture. The molecular mechanismsunderlying the pleiotropic effects of sex-hormones in non-reproductivetissues are only beginning to be understood, but it is clear thatphysiologic concentrations of androgens and estrogens play an importantrole in maintaining bone homeostasis throughout the life-cycle.Consequently, when androgen or estrogen deprivation occurs there is aresultant increase in the rate of bone remodeling that tilts the balanceof resorption and formation to the favor of resorption that contributesto the overall loss of bone mass. In males, the natural decline insex-hormones at maturity (direct decline in androgens as well as lowerlevels of estrogens derived from peripheral aromatization of androgens)is associated with the frailty of bones. This effect is also observed inmales who have been castrated.

Androgen decline in the aging male (ADAM) refers to a progressivedecrease in androgen production, common in males after middle age. Thesyndrome is characterized by alterations in the physical andintellectual domains that correlate with and can be corrected bymanipulation of the androgen milieu. ADAM is characterized biochemicallyby a decrease not only in serum androgen, but also in other hormones,such as growth hormone, melatonin and dehydroepiandrosterone. Clinicalmanifestations include fatigue, depression, decreased libido, sexualdysfunction, erectile dysfunction, hypogonadism, osteoporosis, hairloss, obesity, sarcopenia, osteopenia, benign prostate hyperplasia, andalterations in mood and cognition.

Androgen Deficiency in Female (ADWF) refers to a variety ofhormone-related conditions including, common in females after middleages. The syndrome is characterized by sexual dysfunction, decreasedsexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis,alterations in cognition and mood, anemia, depression, anemia, hairloss, obesity, endometriosis, breast cancer, uterine cancer and ovariancancer.

Muscle wasting refers to the progressive loss of muscle mass and/or tothe progressive weakening and degeneration of muscles, including theskeletal or voluntary muscles, which control movement, cardiac muscles,which control the heart (cardiomyopathics), and smooth muscles. Chronicmuscle wasting is a chronic condition (i.e. persisting over a longperiod of time) characterized by progressive loss of muscle mass,weakening and degeneration of muscle. The loss of muscle mass thatoccurs during muscle wasting can be characterized by a muscle proteinbreakdown or degradation. Protein degradation occurs because of anunusually high rate of protein degradation, an unusually low rate ofprotein synthesis, or a combination of both. Protein degradation,whether caused by a high degree of protein degradation or a low degreeof protein synthesis, leads to a decrease in muscle mass and to musclewasting. Muscle wasting is associated with chronic, neurological,genetic or infectious pathologies, diseases, illnesses or conditions.These include Muscular Dystrophies such as Duchenne Muscular Dystrophyand Myotonic Dystrophy; Muscle Atrophies such as Post-Polio MuscleAtrophy (PPMA); Cachexias such as Cardiac Cachexia, AIDS Cachexia andCancer Cachexia, malnutrition, Leprosy, Diabetes, Renal DiseaseorCHronic Obstructive Pulmonary Disease (COPD), Cancer, end stage Renalfailure, Emphysema, Osteomalacia, HIV Infection, AIDS, andCardiomyopathy, In addition, other circumstances and conditions arelinked to and can cause muscle wasting. These include chronic lower backpain, advanced age, central nervous system (CNS) injury, peripheralnerve injury, spinal cord injuryor Chemical injury, central nervoussystem (CNS) damage, peripheral nerve damage, spinal cord damageorCHemical damage, burns, disuse deconditioning that occurs when a limb isimmobilized, long term hospitalization due to illness or injury, andalcoholism. Muscle wasting, if left unabated, can have dire healthconsequences. For example, the changes that occur during muscle wastingcan lead to a weakened physical state that is detrimental to anindividual's health, resulting in increased susceptibility to infection,poor performance status and susceptibility to injury.

New innovative approaches are urgently needed at both the basic scienceand clinical levels to develop compounds which are useful for a) malecontraception; b) treatment of a variety of hormone-related conditions,for example conditions associated with Androgen Decline in Aging Male(ADAM), such as fatigue, depression, decreased libido, sexualdysfunction, erectile dysfunction, hypogonadism, osteoporosis, hairloss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benignprostate hyperplasia, alterations in mood and cognition and prostatecancer; c) treatment of conditions associated with ADIF, such as sexualdysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of acute and/orchronic muscular wasting conditions; e) preventing and/or treating dryeye conditions; f) oral androgen replacement therapy; and/or g)decreasing the incidence of, halting or causing a regression of prostatecancer.

SUMMARY OF THE INVENTION

This invention provides a class of androgen receptor targeting agents(ARTA). The agents define a new subclass of compounds, which areselective androgen receptor modulators (SARM). Several of the SARMcompounds have been found to have an unexpected androgenic and anabolicactivity of a nonsteroidal ligand for the androgen receptor. Other SARMcompounds have been found to have an unexpected antiandrogenic activityof a nonsteroidal ligand for the androgen receptor. The SARM compounds,either alone or as a composition, are useful for a) male contraception;b) treatment of a variety of hormone-related conditions, for exampleconditions associated with Androgen Decline in Aging Male (ADAM), suchas fatigue, depression, decreased libido, sexual dysfunction, erectiledysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity,sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia,alterations in mood and cognition and prostate cancer; c) treatment ofconditions associated with Androgen Decline in Female (ADIF), such assexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of acute and/orchronic muscular wasting conditions; e) preventing and/or treating dryeye conditions; f) oral androgen replacement therapy; g) decreasing theincidence of, halting or causing a regression of prostate cancer; and/orh) inducing apoptosis in a cancer cell.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula I:

wherein

-   -   G is O or S;    -   X is a bond or CH₂;    -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   Q is alkyl, F, Cl, Br, I, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂,        NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R or SR; or Q together with the benzene ring to which it is        attached is a fused ring system represented by structure A, B or        C:

-   -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃.

In another embodiment, the present invention provides an analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formula I, or any combination thereof.

In one embodiment, X in compound I is a bond. In another embodiment, Xin compound I is a CH₂. In one embodiment, G in compound I is O. Inanother embodiment, T in compound I is OH. In another embodiment, R₁ incompound I is CH₃. In another embodiment, Z in compound I is NO₂. Inanother embodiment, Z in compound I is CN. In another embodiment, Y incompound I is CF₃. In another embodiment, Q in compound I is NHCOCH₃. Inanother embodiment, Q in compound I is F. In another embodiment, Q incompound I is in the para position. In another embodiment, Z in compoundI is in the para position. In another embodiment, Y in compound I is inthe meta position.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula IIa:

wherein G, T, R₁, Z, Y and Q are as defined above for compound I.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula IIb:

wherein G, T, R₁, Z, Y and Q are as defined above for compound I.

In another embodiment, the present invention provides an analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formulas IIa or IIb, or any combination thereof.

In one embodiment, G in compound IIa or IIb is O. In another embodiment,T in compound IIa or IIb is OH. In another embodiment, R₁ in compoundIIa or IIb is CH₃. In another embodiment, Z in compound IIa or IIb isNO₂. In another embodiment, Z in compound IIa or IIb is CN. In anotherembodiment, Y in compound IIa or IIb is CF₃. In another embodiment, Q incompound IIa or IIb is NHCOCH₃. In another embodiment, Q in compound IIaor IIb is F. In another embodiment, Q in compound IIa or IIb is in thepara position. In another embodiment, Z in compound IIa or IIb is in thepara position. In another embodiment, Y in compound IIa or IIb is in themeta position.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula III:

wherein

-   -   G is O or S;    -   X is a bond or CH₂;    -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   Q is alkyl, F, Cl, Br, I, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂,        NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R or SR; or Q together with the benzene ring to which it is        attached is a fused ring system represented by structure A, B or        C:

-   -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃.

In another embodiment, the present invention provides an analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formula III, or any combination thereof.

In one embodiment, X in compound III is a bond. In another embodiment, Xin compound III is a CH₂. In one embodiment, G in compound III is O. Inanother embodiment, T in compound III is OH. In another embodiment, R₁in compound III is CH₃. In another embodiment, Z in compound III is NO₂.In another embodiment, Z in compound III is CN. In another embodiment, Yin compound III is CF₃. In another embodiment, Q in compound III isNHCOCH₃. In another embodiment, Q in compound III is F.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula IVa:

wherein G, T, R₁, Z, Y and Q are as defined above for compound III.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula IVb:

wherein G, T, R₁, Z, Y and Q are as defined above for compound III.

In another embodiment, the present invention provides an analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formula IVa or IVb, or any combination thereof.

In one embodiment, G in compound IVa or IVb is O. In another embodiment,T in compound IVa or IVb is OH. In another embodiment, R₁ in compoundIVa or IVb is CH₃. In another embodiment, Z in compound IVa or IVb isNO₂. In another embodiment, Z in compound IVa or IVb is CN. In anotherembodiment, Y in compound IVa or IVb is CF₃. In another embodiment, Q incompound IVa or IVb is NHCOCH₃. In another embodiment, Q in compound IVaor IVb is F.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula V:

wherein

-   -   X is a bond or CH₂;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, CR₃ or Sn(R)₃;    -   Q is alkyl, F, CT, Br, I, CF₃, CN, CR₃, Sn(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R or        SR; or Q together with the benzene ring to which it is attached        is a fused ring system represented by structure A, B or C:

and

-   -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH.

In another embodiment, the present invention provides an analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formula V, or any combination thereof.

In one embodiment, X in compound V is a bond. In another embodiment, Xin compound V is a CH₂. In another embodiment, Z in compound III is NO₂.In another embodiment, Z in compound V is CN. In another embodiment, Yin compound V is CF₃. In another embodiment, Q in compound V is NHCOCH₃.In another embodiment, Q in compound V is F.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula Via:

wherein Z, Y and Q are as defined above for compound V.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula VIb.

wherein Z, Y and Q are as defined above for compound V.

In another embodiment, the present invention provides an analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formula VIa or VIb, or any combination thereof.

In one embodiment, Z in compound VIa or VIb is NO₂. In anotherembodiment, Z in compound VIa or VIb is CN. In another embodiment, Y incompound VIa or VIb is CF₃. In another embodiment, Q in compound VIa orVIb is NHCOCH₃. In another embodiment, Q in compound VIa or VIb is F.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula VIIa.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula VIIb.

In another embodiment, the present invention provides an analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formula VIIa or VIIb, or any combination thereof.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula VIIIa.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula VIIIb.

In another embodiment, the present invention provides an analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formula VIIIa or VIIb, or any combination thereof.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula IXa

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula IXb.

In another embodiment, the present invention provides an analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formula IXa or IXb, or any combination thereof.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula Xa.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula Xb.

In another embodiment, the present invention provides an analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formula Xa or Xb, or any combination thereof.

In one embodiment, the SARM compound of any of formulas I-X is anandrogen receptor agonist. In another embodiment, the SARM compound ofany of formulas I-X is an androgen receptor antagonist.

In one embodiment, the present invention provides a compositioncomprising the selective androgen receptor modulator compound of any offormulas I-X and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or any combination thereof; and asuitable carrier or diluent.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising the selective androgen receptor modulatorcompound of any of formulas I-X and/or its analog, derivative, isomer,metabolite, pharmaceutical product, hydrate or N-oxide or anycombination thereof; and a suitable carrier or diluent.

In another embodiment, the present invention provides a method ofbinding a selective androgen receptor modulator compound to an androgenreceptor, comprising the step of contacting the androgen receptor withthe selective androgen receptor modulator compound of any of formulasI-X and/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug,polymorph, crystal or any combination thereof, in an amount effective tobind the selective androgen receptor modulator compound to the androgenreceptor.

In another embodiment, the present invention provides a method ofsuppressing spermatogenesis in a subject comprising contacting anandrogen receptor of the subject with the selective androgen receptormodulator compound of any of formulas I-X and/or its analog, derivative,isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, prodrug, polymorph, crystal or anycombination thereof, in an amount effective to suppress spermproduction.

In another embodiment, the present invention provides a method ofcontraception in a male subject, comprising the step of administering tothe subject the selective androgen receptor modulator compound of any offormulas I-X and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or any combination thereof, in anamount effective to suppress sperm production in the subject, therebyeffecting contraception in the subject.

In another embodiment, the present invention provides a method ofhormone therapy comprising the step of contacting an androgen receptorof a subject with the selective androgen receptor modulator compound ofany of formulas I-X and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or any combination thereof, in anamount effective to effect a change in an androgen-dependent condition.

In another embodiment, the present invention provides a method ofhormone replacement therapy comprising the step of contacting anandrogen receptor of a subject with the selective androgen receptormodulator compound of any of formulas I-X and/or its analog, derivative,isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, prodrug, polymorph, crystal or anycombination thereof, in an amount effective to effect a change in anandrogen-dependent condition.

In another embodiment, the present invention provides a method oftreating a subject having a hormone related condition, comprising thestep of administering to the subject the selective androgen receptormodulator compound of any of formulas I-X and/or its analog, derivative,isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, prodrug, polymorph, crystal or anycombination thereof, in an amount effective to effect a change in anandrogen-dependent condition.

In another embodiment, the present invention provides a method oftreating a subject suffering from prostate cancer, comprising the stepof administering to said subject the selective androgen receptormodulator compound of formulas I-X and/or its analog, derivative,isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, prodrug, polymorph, crystal or anycombination thereof, in an amount effective to treat prostate cancer inthe subject.

In another embodiment, the present invention provides a method ofpreventing prostate cancer in a subject, comprising the step ofadministering to the subject the selective androgen receptor modulatorcompound of formulas I-X and/or its analog, derivative, isomer,metabolite, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, prodrug, polymorph, crystal or any combinationthereof, in an amount effective to prevent prostate cancer in thesubject.

In another embodiment, the present invention provides a method ofdelaying the progression of prostate cancer in a subject suffering fromprostate cancer, comprising the step of administering to said subjectthe selective androgen receptor modulator compound of formulas I-Xand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug,polymorph, crystal or any combination thereof, in an amount effective todelay the progression of prostate cancer in the subject.

In another embodiment, the present invention provides a method ofpreventing the recurrence of prostate cancer in a subject suffering fromprostate cancer, comprising the step of administering to said subjectthe selective androgen receptor modulator compound of formulas I-Xand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug,polymorph, crystal or any combination thereof, in an amount effective toprevent the recurrence of prostate cancer in the subject.

In another embodiment, the present invention provides a method oftreating the recurrence of prostate cancer in a subject suffering fromprostate cancer, comprising the step of administering to said subjectthe selective androgen receptor modulator compound of formulas I-Xand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug,polymorph, crystal or any combination thereof, in an amount effective totreat the recurrence of prostate cancer in the subject.

In another embodiment, the present invention provides a method oftreating a dry eye condition in a subject suffering from dry eyes,comprising the step of contacting an androgen receptor of a subject withthe selective androgen receptor modulator compound of any of formulasI-X and/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug,polymorph, crystal or any combination thereof, in an amount effective totreat dry eyes in the subject.

In another embodiment, the present invention provides a method ofpreventing a dry eye condition in a subject, comprising the step ofcontacting an androgen receptor of a subject with the selective androgenreceptor modulator compound of any of formulas I-X and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal orany combination thereof, in an amount effective to prevent dry eyes inthe subject.

In another embodiment, the present invention provides a method ofinducing apoptosis in a cancer cell, comprising the step of contactingthe cell with the selective androgen receptor modulator compound of anyof formulas I-X and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or any combination thereof, in anamount effective to induce apoptosis in the cancer cell.

The novel selective androgen receptor modulator compounds of the presentinvention, either alone or as a pharmaceutical composition, are usefulfor a) male contraception; b) treatment of a variety of hormone-relatedconditions, for example conditions associated with ADAM, such asfatigue, depression, decreased libido, sexual dysfunction, erectiledysfunction, hypogonadism, osteoporosis, hair loss, obesity, sarcopenia,osteopenia, benign prostate hyperplasia, and alterations in mood andcognition; c) treatment of conditions associated with ADIF, such assexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of acute and/orchronic muscular wasting conditions; e) preventing and/or treating dryeye conditions; f) oral androgen replacement therapy; g) decreasing theincidence of, halting or causing a regression of prostate cancer; and/orh) inducing apoptosis in a cancer cell.

The selective androgen receptor modulator compounds of the presentinvention offer a significant advance over steroidal androgen treatment.Several of the selective androgen receptor modulator compounds of thepresent invention have unexpected androgenic and anabolic activity of anonsteroidal ligand for the androgen receptor. Other selective androgenreceptor modulator compounds of the present invention have unexpectedantiandrogenic activity of a nonsteroidal ligand for the androgenreceptor. Thus, treatment with the selective androgen receptor modulatorcompounds of the present invention will not be accompanied by seriousside effects, inconvenient modes of administration, or high costs andwill still have the advantages of oral bioavailability, lack ofcross-reactivity with other steroid receptors, and long biologicalhalf-lives.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, this invention provides a class of androgen receptortargeting agents (ARTA). The agents define a new subclass of compounds,which are selective androgen receptor modulators (SARM). Several of theSARM compounds have been found to have an unexpected androgenic andanabolic activity of a nonsteroidal ligand for the androgen receptor.Other SARM compounds have been found to have an unexpectedantiandrogenic activity of a nonsteroidal ligand for the androgenreceptor. The SARM compounds, either alone or as a composition, areuseful for a) male contraception; b) treatment of a variety ofhormone-related conditions, for example conditions associated withAndrogen Decline in Aging Male (ADAM), such as fatigue, depression,decreased libido, sexual dysfunction, erectile dysfunction,hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia,osteopenia, osteoporosis, benign prostate hyperplasia, alterations inmood and cognition and prostate cancer; c) treatment of conditionsassociated with Androgen Decline in Female (ADIF), such as sexualdysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of acute and/orchronic muscular wasting conditions; e) preventing and/or treating dryeye conditions; f) oral androgen replacement therapy; g) decreasing theincidence of, halting or causing a regression of prostate cancer; and/orh) inducing apoptosis in a cancer cell.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula I:

wherein

-   -   G is O or S;    -   X is a bond or CH₂;    -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   Q is alkyl, F, Cl, Br, I, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂,        NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R or SR; or Q together with the benzene ring to which it is        attached is a fused ring system represented by structure A, B or        C:

-   -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃.

In one embodiment, this invention provides an analog of the compound offormula I. In another embodiment, this invention provides a derivativeof the compound of formula I. In another embodiment, this inventionprovides an isomer of the compound of formula I. In another embodiment,this invention provides a metabolite of the compound of formula I. Inanother embodiment, this invention provides a pharmaceuticallyacceptable salt of the compound of formula I. In another embodiment,this invention provides a pharmaceutical product of the compound offormula I. In another embodiment, this invention provides a hydrate ofthe compound of formula I. In another embodiment, this inventionprovides an N-oxide of the compound of formula I. In another embodiment,this invention provides an impurity of the compound of formula I. Inanother embodiment, this invention provides a prodrug of the compound offormula I. In another embodiment, this invention provides a polymorph ofthe compound of formula I. In another embodiment, this inventionprovides a crystal of the compound of formula I. In another embodiment,this invention provides a combination of any of an analog, derivative,metabolite, isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formula I.

In one embodiment, X in compound I is a bond. In another embodiment, Xin compound I is a CH₂. In one embodiment, G in compound I is O. Inanother embodiment, T in compound I is OH. In another embodiment, R₁ incompound I is CH₃. In another embodiment, Z in compound I is NO₂. Inanother embodiment, Z in compound I is CN. In another embodiment, Y incompound I is CF₃. In another embodiment, Q in compound I is NHCOCH₃. Inanother embodiment, Q in compound I is F. In another embodiment, Q incompound I is in the para position. In another embodiment, Z in compoundI is in the para position. In another embodiment, Y in compound I is inthe meta position.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula IIa:

wherein G, T, R₁, Z, Y and Q are as defined above for compound I.

In one embodiment, this invention provides an analog of the compound offormula IIa. In another embodiment, this invention provides a derivativeof the compound of formula IIa. In another embodiment, this inventionprovides an isomer of the compound of formula IIa. In anotherembodiment, this invention provides a metabolite of the compound offormula IIa. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula IIa. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula IIa. In another embodiment, this inventionprovides a hydrate of the compound of formula IIa. In anotherembodiment, this invention provides an N-oxide of the compound offormula IIa. In another embodiment, this invention provides an impurityof the compound of formula IIa. In another embodiment, this inventionprovides a prodrug of the compound of formula IIa. In anotherembodiment, this invention provides a polymorph of the compound offormula IIa. In another embodiment, this invention provides a crystal ofthe compound of formula IIa In another embodiment, this inventionprovides a combination of any of an analog, derivative, metabolite,isomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, impurity, prodrug, polymorph or crystal of thecompound of formula IIa.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula IIb:

wherein G, T, R₁, Z, Y and Q are as defined above for compound I.

In one embodiment, this invention provides an analog of the compound offormula IIb. In another embodiment, this invention provides a derivativeof the compound of formula IIb. In another embodiment, this inventionprovides an isomer of the compound of formula IIb. In anotherembodiment, this invention provides a metabolite of the compound offormula IIb. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula IIb. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula IIb. In another embodiment, this inventionprovides a hydrate of the compound of formula IIb. In anotherembodiment, this invention provides an N-oxide of the compound offormula IIb. In another embodiment, this invention provides an impurityof the compound of formula IIb. In another embodiment, this inventionprovides a prodrug of the compound of formula IIb. In anotherembodiment, this invention provides a polymorph of the compound offormula IIb. In another embodiment, this invention provides a crystal ofthe compound of formula IIb. In another embodiment, this inventionprovides a combination of any of an analog, derivative, metabolite,isomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, impurity, prodrug, polymorph or crystal of thecompound of formula IIb.

In one embodiment, G in compound IIa or IIb is O. In another embodiment,T in compound IIa or IIb is OH. In another embodiment, R₁ in compoundIIa or IIb is CH₃. In another embodiment, Z in compound IIa or IIb isNO₂. In another embodiment, Z in compound IIa or IIb is CN. In anotherembodiment, Y in compound IIa or IIb is CF₃. In another embodiment, Q incompound IIa or IIb is NHCOCH₃. In another embodiment, Q in compound IIaor IIb is F. In another embodiment, Q in compound IIa or IIb is in thepara position. In another embodiment, Z in compound IIa or IIb is in thepara position. In another embodiment, Y in compound IIa or IIb is in themeta position.

The substituents Z and Y can be in any position of the ring carryingthese substituents (hereinafter “A ring”). In one embodiment, thesubstituent Z is in the para position of the A ring. In anotherembodiment, the substituent Y is in the meta position of the A ring. Inanother embodiment, the substituent Z is in the para position of the Aring and substituent Y is in the meta position of the A ring.

The substituent Q can be in any position of the ring carrying thissubstituent (hereinafter “B ring”). In one embodiment, the substituent Qis in the para position of the B ring. In another embodiment, thesubstituent Q is NHCOCH₃ and is in the para position of the B ring. Inanother embodiment, the substituent Q is F and is in the para positionof the B ring.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula III:

wherein

-   -   G is O or S;    -   X is a bond or CH₂;    -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   Q is alkyl, F, Cl, Br, I, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂,        NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R or SR; or Q together with the benzene ring to which it is        attached is a fused ring system represented by structure A, B or        C:

-   -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃.

In one embodiment, this invention provides an analog of the compound offormula III. In another embodiment, this invention provides a derivativeof the compound of formula III. In another embodiment, this inventionprovides an isomer of the compound of formula III. In anotherembodiment, this invention provides a metabolite of the compound offormula III. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula III. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula III. In another embodiment, this inventionprovides a hydrate of the compound of formula III. In anotherembodiment, this invention provides an N-oxide of the compound offormula III. In another embodiment, this invention provides an impurityof the compound of formula III. In another embodiment, this inventionprovides a prodrug of the compound of formula III. In anotherembodiment, this invention provides a polymorph of the compound offormula III. In another embodiment, this invention provides a crystal ofthe compound of formula III. In another embodiment, this inventionprovides a combination of any of an analog, derivative, metabolite,isomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, impurity, prodrug, polymorph or crystal of thecompound of formula III.

In one embodiment, X in compound III is a bond. In another embodiment, Xin compound III is a CH₂. In one embodiment, G in compound III is O. Inanother embodiment, T in compound III is OH. In another embodiment, R₁in compound III is CH₃. In another embodiment, Z in compound III is NO₂.In another embodiment, Z in compound III is CN. In another embodiment, Yin compound III is CF₃. In another embodiment, Q in compound III isNHCOCH₃. In another embodiment, Q in compound III is F.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula IVa:

wherein G, T, R₁, Z, Y and Q are as defined above for compound III.

In one embodiment, this invention provides an analog of the compound offormula IVa. In another embodiment, this invention provides a derivativeof the compound of formula IVa. In another embodiment, this inventionprovides an isomer of the compound of formula IVa. In anotherembodiment, this invention provides a metabolite of the compound offormula IVa. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula IVa. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula IVa. In another embodiment, this inventionprovides a hydrate of the compound of formula IVa. In anotherembodiment, this invention provides an N-oxide of the compound offormula IVa. In another embodiment, this invention provides an impurityof the compound of formula IVa. In another embodiment, this inventionprovides a prodrug of the compound of formula IVa. In anotherembodiment, this invention provides a polymorph of the compound offormula IVa. In another embodiment, this invention provides a crystal ofthe compound of formula IVa. In another embodiment, this inventionprovides a combination of any of an analog, derivative, metabolite,isomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, impurity, prodrug, polymorph or crystal of thecompound of formula IVa.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula IVb:

wherein G, T, R₁, Z, Y and Q are as defined above for compound III.

In one embodiment, this invention provides an analog of the compound offormula IVb. In another embodiment, this invention provides a derivativeof the compound of formula IVb. In another embodiment, this inventionprovides an isomer of the compound of formula IVb. In anotherembodiment, this invention provides a metabolite of the compound offormula IVb. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula IVb. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula IVb. In another embodiment, this inventionprovides a hydrate of the compound of formula IVb. In anotherembodiment, this invention provides an N-oxide of the compound offormula IVb. In another embodiment, this invention provides an impurityof the compound of formula IVb. In another embodiment, this inventionprovides a prodrug of the compound of formula IVb. In anotherembodiment, this invention provides a polymorph of the compound offormula IVb. In another, embodiment, this invention provides a crystalof the compound of formula IVb. In another embodiment, this inventionprovides a combination of any of an analog, derivative, metabolite,isomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, impurity, prodrug, polymorph or crystal of thecompound of formula IVb.

In one embodiment, G in compound IVa or IVb is O. In another embodiment,T in compound IVa or IVb is OH. In another embodiment, R₁ in compoundIVa or IVb is CH₃. In another embodiment, Z in compound IVa or IVb isNO₂. In another embodiment, Z in compound IVa or IVb is CN. In anotherembodiment, Y in compound IVa or IVb is CF₃. In another embodiment, Q incompound IVa or IVb is NHCOCH₃. In another embodiment, Q in compound IVaor IVb is F.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula V:

wherein

-   -   X is a bond or CH₂;    -   Z is NO₂, CN, COOH, COR, NHCOR or CONHR;    -   Y is CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃;    -   Q is alkyl, F, Cl, Br, I, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂,        NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR,        NHCSCH₃, NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R,        SO₂R or SR; or Q together with the benzene ring to which it is        attached is a fused ring system represented by structure A, B or        C:

and

-   -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH.

In one embodiment, this invention provides an analog of the compound offormula V. In another embodiment, this invention provides a derivativeof the compound of formula V. In another embodiment, this inventionprovides an isomer of the compound of formula V. In another embodiment,this invention provides a metabolite of the compound of formula V. Inanother embodiment, this invention provides a pharmaceuticallyacceptable salt of the compound of formula V. In another embodiment,this invention provides a pharmaceutical product of the compound offormula V. In another embodiment, this invention provides a hydrate ofthe compound of formula V. In another embodiment, this inventionprovides an N-oxide of the compound of formula V. In another embodiment,this invention provides an impurity of the compound of formula V. Inanother embodiment, this invention provides a prodrug of the compound offormula V. In another embodiment, this invention provides a polymorph ofthe compound of formula V. In another embodiment, this inventionprovides a crystal of the compound of formula V. In another embodiment,this invention provides a combination of any of an analog, derivative,metabolite, isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formula V.

In one embodiment, X in compound V is a bond. In another embodiment, Xin compound V is a CH₂. In another embodiment, Z in compound III is NO₂.In another embodiment, Z in compound V is CN. In another embodiment, Yin compound V is CF₃. In another embodiment, Q in compound V is NHCOCH₃.In another embodiment, Q in compound V is F.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula VIa.

wherein Z, Y and Q are as defined above for compound V.

In one embodiment, this invention provides an analog of the compound offormula VIa. In another embodiment, this invention provides a derivativeof the compound of formula VIa. In another embodiment, this inventionprovides an isomer of the compound of formula VIa. In anotherembodiment, this invention provides a metabolite of the compound offormula VIa. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula VIa. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula VIa. In another embodiment, this inventionprovides a hydrate of the compound of formula VIa. In anotherembodiment, this invention provides an N-oxide of the compound offormula VIa. In another embodiment, this invention provides an impurityof the compound of formula VIa. In another embodiment, this inventionprovides a prodrug of the compound of formula VIa. In anotherembodiment, this invention provides a polymorph of the compound offormula VIa. In another embodiment, this invention provides a crystal ofthe compound of formula VIa. In another embodiment, this inventionprovides a combination of any of an analog, derivative, metabolite,isomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, impurity, prodrug, polymorph or crystal of thecompound of formula VIa.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula VIb.

wherein Z, Y and Q are as defined above for compound V.

In one embodiment, this invention provides an analog of the compound offormula VIb. In another embodiment, this invention provides a derivativeof the compound of formula VIb. In another embodiment, this inventionprovides an isomer of the compound of formula VIb. In anotherembodiment, this invention provides a metabolite of the compound offormula VIb. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula VIb. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula VIb. In another embodiment, this inventionprovides a hydrate of the compound of formula VIb. In anotherembodiment, this invention provides an N-oxide of the compound offormula VIb. In another embodiment, this invention provides an impurityof the compound of formula VIb. In another embodiment, this inventionprovides a prodrug of the compound of formula VIb. In anotherembodiment, this invention provides a polymorph of the compound offormula VIb. In another embodiment, this invention provides a crystal ofthe compound of formula VIb. In another embodiment, this inventionprovides a combination of any of an analog, derivative, metabolite,isomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, impurity, prodrug, polymorph or crystal of thecompound of formula VIb.

In one embodiment, Z in compound VIa or VIb is NO₂. In anotherembodiment, Z in compound VIa or VIb is CN. In another embodiment, Y incompound VIa or VIb is CF₃. In another embodiment, Q in compound VIa orVIb is NHCOCH₃. In another embodiment, Q in compound VIa or VIb is F.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula VIIa.

In one embodiment, this invention provides an analog of the compound offormula VIIa. In another embodiment, this invention provides aderivative of the compound of formula VIIa. In another embodiment, thisinvention provides an isomer of the compound of formula VIIa. In anotherembodiment, this invention provides a metabolite of the compound offormula VIIa. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula VIIa. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula VIIa. In another embodiment, this inventionprovides a hydrate of the compound of formula VIIa. In anotherembodiment, this invention provides an N-oxide of the compound offormula VIIa. In another embodiment, this invention provides an impurityof the compound of formula VIIa. In another embodiment, this inventionprovides a prodrug of the compound of formula VIIa. In anotherembodiment, this invention provides a polymorph of the compound offormula VIIa. In another embodiment, this invention provides a crystalof the compound of formula VIIa. In another embodiment, this inventionprovides a combination of any of an analog, derivative, metabolite,isomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, impurity, prodrug, polymorph or crystal of thecompound of formula VIIa.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula VIIb.

In one embodiment, this invention provides an analog of the compound offormula VIIb. In another embodiment, this invention provides aderivative of the compound of formula VIIb. In another embodiment, thisinvention provides an isomer of the compound of formula VIIb. In anotherembodiment, this invention provides a metabolite of the compound offormula VIIb. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula VIIb. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula VIIb. In another embodiment, this inventionprovides a hydrate of the compound of formula VIIb. In anotherembodiment, this invention provides an N-oxide of the compound offormula VIIb. In another embodiment, this invention provides an impurityof the compound of formula VIIb. In another embodiment, this inventionprovides a prodrug of the compound of formula VIIb. In anotherembodiment, this invention provides a polymorph of the compound offormula VIIb. In another embodiment, this invention provides a crystalof the compound of formula VIIb. In another embodiment, this inventionprovides a combination of any of an analog, derivative, metabolite,isomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, impurity, prodrug, polymorph or crystal of thecompound of formula VIIb.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula VIIIa.

In one embodiment, this invention provides an analog of the compound offormula VIIIa. In another embodiment, this invention provides aderivative of the compound of formula VIIIa. In another embodiment, thisinvention provides an isomer of the compound of formula VIIIa. Inanother embodiment, this invention provides a metabolite of the compoundof formula VIIIa. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula VIIIa. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula VIIIa. In another embodiment, this inventionprovides a hydrate of the compound of formula VIIIa. In anotherembodiment, this invention provides an N-oxide of the compound offormula VIIIa. In another embodiment, this invention provides animpurity of the compound of formula VIIIa. In another embodiment, thisinvention provides a prodrug of the compound of formula VIIIa. Inanother embodiment, this invention provides a polymorph of the compoundof formula VIIIa. In another embodiment, this invention provides acrystal of the compound of formula VIIIa. In another embodiment, thisinvention provides a combination of any of an analog, derivative,metabolite, isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formula VIIIa.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula VIIIb.

In one embodiment, this invention provides an analog of the compound offormula VIIIb. In another embodiment, this invention provides aderivative of the compound of formula VIIIb. In another embodiment, thisinvention provides an isomer of the compound of formula VIIIb. Inanother embodiment, this invention provides a metabolite of the compoundof formula VIIIb. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula VIIIb. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula VIIIb. In another embodiment, this inventionprovides a hydrate of the compound of formula VIIIb. In anotherembodiment, this invention provides an N-oxide of the compound offormula VIIIb. In another embodiment, this invention provides animpurity of the compound of formula VIIIb. In another embodiment, thisinvention provides a prodrug of the compound of formula VIIIb. Inanother embodiment, this invention provides a polymorph of the compoundof formula VIIIb. In another embodiment, this invention provides acrystal of the compound of formula VIIIb. In another embodiment, thisinvention provides a combination of any of an analog, derivative,metabolite, isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, impurity, prodrug, polymorph or crystal ofthe compound of formula VIIIb.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula IXa.

In one embodiment, this invention provides an analog of the compound offormula IXa. In another embodiment, this invention provides a derivativeof the compound of formula IXa. In another embodiment, this inventionprovides an isomer of the compound of formula IXa. In anotherembodiment, this invention provides a metabolite of the compound offormula IXa. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula IXa. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula IXa. In another embodiment, this inventionprovides a hydrate of the compound of formula IXa. In anotherembodiment, this invention provides an N-oxide of the compound offormula IXa. In another embodiment, this invention provides an impurityof the compound of formula IXa. In another embodiment, this inventionprovides a prodrug of the compound of formula IXa. In anotherembodiment, this invention provides a polymorph of the compound offormula IXa. In another embodiment, this invention provides a crystal ofthe compound of formula IXa. In another embodiment, this inventionprovides a combination of any of an analog, derivative, metabolite,isomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, impurity, prodrug, polymorph or crystal of thecompound of formula IXa.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula IXb.

In one embodiment, this invention provides an analog of the compound offormula IXb. In another embodiment, this invention provides a derivativeof the compound of formula IXb. In another embodiment, this inventionprovides an isomer of the compound of formula IXb. In anotherembodiment, this invention provides a metabolite of the compound offormula IXb. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula IXb. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula IXb. In another embodiment, this inventionprovides a hydrate of the compound of formula IXb. In anotherembodiment, this invention provides an N-oxide of the compound offormula IXb. In another embodiment, this invention provides an impurityof the compound of formula IXb. In another embodiment, this inventionprovides a prodrug of the compound of formula IXb. In anotherembodiment, this invention provides a polymorph of the compound offormula IXb. In another embodiment, this invention provides a crystal ofthe compound of formula IXb. In another embodiment, this inventionprovides a combination of any of an analog, derivative, metabolite,isomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, impurity, prodrug, polymorph or crystal of thecompound of formula IXb.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula Xa.

In one embodiment, this invention provides an analog of the compound offormula Xa. In another embodiment, this invention provides a derivativeof the compound of formula Xa. In another embodiment, this inventionprovides an isomer of the compound of formula Xa. In another embodiment,this invention provides a metabolite of the compound of formula Xa. Inanother embodiment, this invention provides a pharmaceuticallyacceptable salt of the compound of formula Xa. In another embodiment,this invention provides a pharmaceutical product of the compound offormula Xa. In another embodiment, this invention provides a hydrate ofthe compound of formula Xa. In another embodiment, this inventionprovides an N-oxide of the compound of formula Xa. In anotherembodiment, this invention provides an impurity of the compound offormula Xa. In another embodiment, this invention provides a prodrug ofthe compound of formula Xa. In another embodiment, this inventionprovides a polymorph of the compound of formula Xa. In anotherembodiment, this invention provides a crystal of the compound of formulaXa. In another embodiment, this invention provides a combination of anyof an analog, derivative, metabolite, isomer, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, impurity,prodrug, polymorph or crystal of the compound of formula Xa.

In one embodiment, the present invention provides a selective androgenreceptor modulator (SARM) compound represented by the structure offormula Xb.

In one embodiment, this invention provides an analog of the compound offormula Xb. In another embodiment, this invention provides a derivativeof the compound of formula Xb. In another embodiment, this inventionprovides an isomer of the compound of formula Xb. In another embodiment,this invention provides a metabolite of the compound of formula Xb. Inanother embodiment, this invention provides a pharmaceuticallyacceptable salt of the compound of formula Xb. In another embodiment,this invention provides a pharmaceutical product of the compound offormula Xb. In another embodiment, this invention provides a hydrate ofthe compound of formula Xb. In another embodiment, this inventionprovides an N-oxide of the compound of formula Xb. In anotherembodiment, this invention provides an impurity of the compound offormula Xb. In another embodiment, this invention provides a prodrug ofthe compound of formula Xb. In another embodiment, this inventionprovides a polymorph of the compound of formula Xb. In anotherembodiment, this invention provides a crystal of the compound of formulaXb. In another embodiment, this invention provides a combination of anyof an analog, derivative, metabolite, isomer, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, impurity,prodrug, polymorph or crystal of the compound of formula Xb.

The substituent R is defined herein as an alkyl, haloalkyl, dihaloalkyl,trihaloalkyl, CH₂F, CHF₂, CF₃, CF₂CF₃; aryl, phenyl, F, Cl, Br, I,alkenyl, or hydroxyl (OH).

An “alkyl” group refers to a saturated aliphatic hydrocarbon, includingstraight-chain, branched-chain and cyclic alkyl groups. In oneembodiment, the alkyl group has 1-12 carbons. In another embodiment, thealkyl group has 1-7 carbons. In another embodiment, the alkyl group has1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons. Thealkyl group may be unsubstituted or substituted by one or more groupsselected from halogen (e.g. F, Cl, Br, I), hydroxy, alkoxy carbonyl,amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino,carboxyl, thio and thioalkyl.

A “haloalkyl” group refers to an alkyl group as defined above, which issubstituted by one or more halogen atoms, e.g. by F, Cl, Br or I. A“halogen” refers to elements of Group VII or the periodic table, e.g. F,Cl, Br or I.

An “aryl” group refers to an aromatic group having at least onecarbocyclic aromatic group or heterocyclic aromatic group, which may beunsubstituted or substituted by one or more groups selected from halogen(e.g. F, Cl, Br, I), haloalkyl, hydroxy, alkoxy carbonyl, amido,alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino,carboxy or thio or thioalkyl. Nonlimiting examples of aryl rings arephenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl,pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, andthe like.

A “hydroxyl” group refers to an OH group. An “alkenyl” group refers to agroup having at least one carbon to carbon double bond.

An “arylalkyl” group refers to an alkyl bound to an aryl, wherein alkyland aryl are as defined above. An example of an aralkyl group is abenzyl group.

As contemplated herein, the present invention relates to the use of aSARM compound and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph or crystal or combinations thereof. In oneembodiment, the invention relates to the use of an analog of the SARMcompound. In another embodiment, the invention relates to the use of aderivative of the SARM compound. In another embodiment, the inventionrelates to the use of an isomer of the SARM compound. In anotherembodiment, the invention relates to the use of a metabolite of the SARMcompound. In another embodiment, the invention relates to the use of apharmaceutically acceptable salt of the SARM compound. In anotherembodiment, the invention relates to the use of a pharmaceutical productof the SARM compound. In another embodiment, the invention relates tothe use of a hydrate of the SARM compound. In another embodiment, theinvention relates to the use of an N-oxide of the SARM compound. Inanother embodiment, the invention relates to the use of a prodrug of theSARM compound. In another embodiment, the invention relates to the useof a polymorph of the SARM compound. In another embodiment, theinvention relates to the use of a crystal of the SARM compound. Inanother embodiment, the invention relates to the use of any of acombination of an analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate, orN-oxide, prodrug, polymorph or crystal of the SARM compounds of thepresent invention.

As defined herein, the term “isomer” includes, but is not limited to,optical isomers and analogs, structural isomers and analogs,conformational isomers and analogs, and the like.

In one embodiment, this invention encompasses the use of various opticalisomers of the SARM compounds. It will be appreciated by those skilledin the art that the SARM compounds of the present invention contain atleast one chiral center. Accordingly, the SARM compounds used in themethods of the present invention may exist in, and be isolated in,optically-active or racemic forms. Some compounds may also exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, which form possessesproperties useful in the methods as described herein. In one embodiment,the SARM compounds are the pure (R)-isomers. In another embodiment, theSARM compounds are the pure (S)-isomers. In another embodiment, the SARMcompounds are a mixture of the (R) and the (S) isomers. In anotherembodiment, the SARM compounds are a racemic mixture comprising an equalamount of the (R) and the (S) isomers. It is well known in the art howto prepare optically-active forms (for example, by resolution of theracemic form by recrystallization techniques, by synthesis fromoptically-active starting materials, by chiral synthesis, or bychromatographic separation using a chiral stationary phase).

The invention includes pharmaceutically acceptable salts ofamino-substituted compounds with organic and inorganic acids, forexample, citric acid and hydrochloric acid. The invention also includesN-oxides of the amino substituents of the compounds described herein.Pharmaceutically acceptable salts can also be prepared from the phenoliccompounds by treatment with inorganic bases, for example, sodiumhydroxide. Also, esters of the phenolic compounds can be made withaliphatic and aromatic carboxylic acids, for example, acetic acid andbenzoic acid esters.

This invention further includes derivatives of the SARM compounds. Theterm “derivatives” includes but is not limited to ether derivatives,acid derivatives, amide derivatives, ester derivatives and the like. Inaddition, this invention further includes hydrates of the SARMcompounds. The term “hydrate” includes but is not limited tohemihydrate, monohydrate, dihydrate, trihydrate and the like.

This invention further includes metabolites of the SARM compounds. Theterm “metabolite” means any substance produced from another substance bymetabolism or a metabolic process.

This invention further includes pharmaceutical products of the SARMcompounds. The term “pharmaceutical product” means a compositionsuitable for pharmaceutical use (pharmaceutical composition), as definedherein.

This invention further includes prodrugs of the SARM compounds. The term“prodrug” means a substance which can be converted in-vivo into abiologically active agent by such reactions as hydrolysis,esterification, desterification, activation, salt formation and thelike.

This invention further includes crystals of the SARM compounds.Furthermore, this invention provides polymorphs of the SARM compounds.The term “crystal” means a substance in a crystalline state. The term“polymorph” refers to a particular crystalline state of a substance,having particular physical properties such as X-ray diffraction, IRspectra, melting point, and the like.

Biological Activity of Selective Androgen Receptor Modulator Compounds

Selective androgen receptor modulator (SARM) compounds are a novel classof androgen receptor targeting agents (“ARTA”), that have previouslybeen shown to be useful for a) male contraception; b) treatment of avariety of hormone-related conditions, for example conditions associatedwith Androgen Decline in Aging Male (ADAM), such as fatigue, depression,decreased libido, sexual dysfunction, erectile dysfunction,hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia,osteopenia, osteoporosis, benign prostate hyperplasia, alterations inmood and cognition and prostate cancer; c) treatment of conditionsassociated with Androgen Decline in Female (ADIF), such as sexualdysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of acute and/orchronic muscular wasting conditions; e) preventing and/or treating dryeye conditions; f) oral androgen replacement therapy; g) decreasing theincidence of, halting or causing a regression of prostate cancer; and/orh) inducing apoptosis in a cancer cell.

As used herein, receptors for extracellular signaling molecules arecollectively referred to as “cell signaling receptors”. Many cellsignaling receptors are transmembrane proteins on a cell surface; whenthey bind an extracellular signaling molecule (i.e., a ligand), theybecome activated so as to generate a cascade of intracellular signalsthat alter the behavior of the cell. In contrast, in some cases, thereceptors are inside the cell and the signaling ligand has to enter thecell to activate them; these signaling molecules therefore must besufficiently small and hydrophobic to diffuse across the plasma membraneof the cell.

Steroid hormones are one example of small hydrophobic molecules thatdiffuse directly across the plasma membrane of target cells and bind tointracellular cell signaling receptors. These receptors are structurallyrelated and constitute the intracellular receptor superfamily (orsteroid-hormone receptor superfamily). Steroid hormone receptors includeprogesterone receptors, estrogen receptors, androgen receptors,glucocorticoid receptors, and mineralocorticoid receptors. The presentinvention is particularly directed to androgen receptors.

In addition to ligand binding to the receptors, the receptors can beblocked to prevent ligand binding. When a substance binds to a receptor,the three-dimensional structure of the substance fits into a spacecreated by the three-dimensional structure of the receptor in a ball andsocket configuration. The better the ball fits into the socket, the moretightly it is held. This phenomenon is called affinity. If the affinityof a substance is greater than the original hormone, it will competewith the hormone and bind the binding site more frequently. Once bound,signals may be sent through the receptor into the cell, causing the cellto respond in some fashion. This is called activation. On activation,the activated receptor then directly regulates the transcription ofspecific genes. But the substance and the receptor may have certainattributes, other than affinity, in order to activate the cell. Chemicalbonds between atoms of the substance and the atoms of the receptors mayform. In some cases, this leads to a change in the configuration of thereceptor, which is enough to begin the activation process (called signaltransduction).

In one embodiment, the present invention is directed to selectiveandrogen receptor modulator compounds which are agonist compounds. Areceptor agonist is a substance which binds receptors and activatesthem. Thus, in one embodiment, the SARM compounds of the presentinvention are useful in binding to and activating steroidal hormonereceptors. In one embodiment, the agonist compound of the presentinvention is an agonist which binds the androgen receptor. In anotherembodiment, the compound has high affinity for the androgen receptor. Inanother embodiment, the agonist compound also has anabolic activity. Inanother embodiment, the present invention provides selective androgenmodulator compounds which have agonistic and anabolic activity of anonsteroidal compound for the androgen receptor.

In another embodiment, the present invention is directed to selectiveandrogen receptor modulator compounds which are antagonist compounds. Areceptor antagonist is a substance which binds receptors and inactivatesthem. Thus, in one embodiment, the SARM compounds of the presentinvention are useful in binding to and inactivating steroidal hormonereceptors. In one embodiment, the antagonist compound of the presentinvention is an antagonist which binds the androgen receptor. In anotherembodiment, the compound has high affinity for the androgen receptor.

In yet another embodiment, the SARM compounds of the present inventioncan be classified as partial AR agonist/antagonists. The SARMs are ARagonists in some tissues, to cause increased transcription ofAR-responsive genes (e.g. muscle anabolic effect). In other tissues,these compounds serve as inhibitors at the AR to prevent agonisticeffects of the native androgens.

Assays to determine whether the compounds of the present invention areAR agonists or antagonists are well known to a person skilled in theart. For example, AR agonistic activity can be determined by monitoringthe ability of the SARM compounds to maintain and/or stimulate thegrowth of AR containing tissue such as prostate and seminal vesicles, asmeasured by weight. AR antagonistic activity can be determined bymonitoring the ability of the SARM compounds to inhibit the growth of ARcontaining tissue.

The compounds of the present invention bind either reversibly orirreversibly to an androgen receptor. In one embodiment, the androgenreceptor is an androgen receptor of a mammal. In another embodiment, theandrogen receptor is an androgen receptor of a human. In one embodiment,the SARM compounds bind reversibly to the androgen receptor of a mammal,for example a human. Reversible binding of a compound to a receptormeans that a compound can detach from the receptor after binding.

In another embodiment, the SARM compounds bind irreversibly to theandrogen receptor of a mammal, for example a human. Thus, in oneembodiment, the compounds of the present invention may contain afunctional group (e.g. affinity label) that allows alkylation of theandrogen receptor (i.e. covalent bond formation). Thus, in this case,the compounds are alkylating agents which bind irreversibly to thereceptor and, accordingly, cannot be displaced by a steroid, such as theendogenous ligands DHT and testosterone. An “alkylating agent” isdefined herein as an agent which alkylates (forms a covalent bond) witha cellular component, such as DNA, RNA or enzyme. It is a highlyreactive chemical that introduces alkyl radicals into biologicallyactive molecules and thereby prevents their proper functioning. Thealkylating moiety is an electrophilic group that interacts withnucleophilic moieties in cellular components.

According to one embodiment of the present invention, a method isprovided for binding the SARM compounds of the present invention to anandrogen receptor by contacting the receptor with a SARM compound and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal or any combination thereof, under conditions effective to causethe selective androgen receptor modulator compound to bind the androgenreceptor. The binding of the selective androgen receptor modulatorcompounds to the androgen receptor enables the compounds of the presentinvention to be useful as a male contraceptive and in a number ofhormone therapies. The agonist compounds bind to and activate theandrogen receptor. The antagonist compounds bind to and inactivate theandrogen receptor. Binding of the agonist or antagonist compounds iseither reversible or irreversible.

According to one embodiment of the present invention, a method isprovided for suppressing spermatogenesis in a subject by contacting anandrogen receptor of the subject with a SARM compound of the presentinvention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or any combination thereof, in anamount effective to bind the selective androgen receptor modulatorcompound to the androgen receptor and suppress spermatogenesis.

In another embodiment, the present invention provides a method ofcontraception in a male subject, comprising the step of administering tothe subject a SARM compound of the present invention, and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal orany combination thereof, in an amount effective to suppress spermproduction in the subject, thereby effecting contraception in thesubject.

According to another embodiment of the present invention, a method isprovided for hormonal therapy in a patient (i.e., one suffering from anandrogen-dependent condition) which includes contacting an androgenreceptor of a patient with a SARM compound of the present inventionand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug,polymorph, crystal or any combination thereof, in an amount effective tobind the selective androgen receptor modulator compound to the androgenreceptor and effect a change in an androgen-dependent condition.

According to another embodiment of the present invention, a method isprovided for hormonal replacement therapy in a patient which includescontacting an androgen receptor of a patient with a SARM compound of thepresent invention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or any combination thereof, in anamount effective to bind the selective androgen receptor modulatorcompound to the androgen receptor and effect a change in anandrogen-dependent condition.

According to another embodiment of the present invention, a method isprovided for treating a subject having a hormone related condition whichincludes administering to the subject a SARM compound of the presentinvention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or any combination thereof, in anamount effective to bind the SARM compound to the androgen receptor andeffect a change in an androgen-dependent condition.

Androgen-dependent conditions which may be treated according to thepresent invention include those conditions which are associated withaging, such as hypogonadism, sarcopenia, erythropoiesis, osteoporosis,and any other conditions determined to be dependent upon low androgen(e.g., testosterone) levels.

According to another embodiment of the present invention, a method isprovided for treating a subject suffering from prostate cancer,comprising the step of administering to the subject a SARM compound ofthe present invention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or any combination thereof, in anamount effective to treat prostate cancer in the subject.

According to another embodiment of the present invention, a method isprovided for preventing prostate cancer in a subject, comprising thestep of administering to the subject a SARM compound of the presentinvention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or any combination thereof, in anamount effective to prevent prostate cancer in the subject.

According to another embodiment of the present invention, a method isprovided for delaying the progression of prostate cancer in a subjectsuffering from prostate cancer, comprising the step of administering tothe subject a SARM compound of the present invention and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal orany combination thereof, in an amount effective to delay the progressionof prostate cancer in the subject.

According to another embodiment of the present invention, a method isprovided for preventing the recurrence of prostate cancer in a subjectsuffering from prostate cancer, comprising the step of administering tothe subject a SARM compound of the present invention and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal orany combination thereof, in an amount effective to prevent therecurrence of prostate cancer in the subject.

According to another embodiment of the present invention, a method isprovided for treating the recurrence of prostate cancer in a subjectsuffering from prostate cancer, comprising the step of administering tothe subject a SARM compound of the present invention and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal orany combination thereof, in an amount effective to treat the recurrenceof prostate cancer in the subject.

Furthermore, stimulation of the Androgen Receptor stimulates theproduction of tears, and thus the SARM compounds of the presentinvention may be used to treat dry eye conditions. Therefore, accordingto another embodiment of the present invention, a method is provided fortreating a dry eye condition in a subject suffering from dry eyes,comprising the step of administering to said subject the selectiveandrogen receptor modulator compound of the present invention and/or itsanalog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal or any combination thereof, in an amount effective to treat dryeyes in the subject.

According to another embodiment of the present invention, a method isprovided for preventing a dry eye condition in a subject, comprising thestep of administering to said subject the selective androgen receptormodulator compound of the present invention and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal orany combination thereof, in an amount effective to prevent dry eyes inthe subject.

In another embodiment, the present invention provides a method ofinducing apoptosis in a cancer cell, comprising the step of contactingthe cell with the selective androgen receptor modulator compound of thepresent invention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or any combination thereof, in anamount effective to induce apoptosis in said cancer cell.

As defined herein, “contacting” means that the SARM compound of thepresent invention is introduced into a sample containing the enzyme in atest tube, flask, tissue cultureor CHip, array, plate, microplate,capillary, or the like, and incubated at a temperature and timesufficient to permit binding of the SARM to the enzyme. Methods forcontacting the samples with the SARM or other specific bindingcomponents are known to those skilled in the art and may be selecteddepending on the type of assay protocol to be run. Incubation methodsare also standard and are known to those skilled in the art.

In another embodiment, the term “contacting” means that the SARMcompound of the present invention is introduced into a subject receivingtreatment, and the SARM compound is allowed to come in contact with theandrogen receptor in vivo.

The term “libido, as used herein, means sexual desire.

The term “erectile”, as used herein, means capable of being erected. Anerectile tissue is a tissue, which is capable of being greatly dilatedand made rigid by the distension of the numerous blood vessels which itcontains.

“Hypogonadism” is a condition resulting from or characterised byabnormally decreased functional activity of the gonads, with retardationof growth and sexual development. “Osteopenia” refers to decreasedcalcification or density of bone. This is a term which encompasses allskeletal systems in which such a condition is noted.

“Osteoporosis” refers to a thinning of the bones with reduction in bonemass due to depletion of calcium and bone protein. Osteoporosispredisposes a person to fractures, which are often slow to heal and healpoorly. Unchecked osteoporosis can lead to changes in posture, physicalabnormality, and decreased mobility.

“BPH (benign prostate hyperplasia)” is a nonmalignant enlargement of theprostate gland, and is the most common non-malignant proliferativeabnormality found in any internal organ and the major cause of morbidityin the adult male. BPH occurs in over 75% of men over 50 years of age,reaching 88% prevalence by the ninth decade. BPH frequently results in agradual squeezing of the portion of the urethra which traverses theprostate (prostatic urethra). This causes patients to experience afrequent urge to urinate because of incomplete emptying of the bladderand urgency of urination. The obstruction of urinary flow can also leadto a general lack of control over urination, including difficultyinitiating urination when desired, as well as difficulty in preventingurinary flow because of the inability to empty urine from the bladder, acondition known as overflow urinary incontinence, which can lead tourinary obstruction and to urinary failure.

“Cognition” refers to the process of knowing, specifically the processof being aware, knowing, thinking, learning and judging. Cognition isrelated to the fields of psychology, linguistics, computer science,neuroscience, mathematics, ethology and philosophy. The term “mood”refers to a temper or state of the mind. As contemplated herein,alterations means any change for the positive or negative, in cognitionand/or mood.

The term “depression” refers to an illness that involves the body, moodand thoughts, that affects the way a person eats, sleeps and the way onefeels about oneself, and thinks about things. The signs and symptoms ofdepression include loss of interest in activities, loss of appetite orovereating, loss of emotional expression, an empty mood, feelings ofhopelessness, pessimism, guilt or helplessness, social withdrawal,fatigue, sleep disturbances, trouble concentrating, remembering, ormaking decisions, restlessness, irritability, headaches, digestivedisorders or chronic pain.

The term “hair loss”, medically known as alopecia, refers to baldness asin the very common type of male-pattern baldness. Baldness typicallybegins with patch hair loss on the scalp and sometimes progresses tocomplete baldness and even loss of body hair. Hair loss affects bothmales and females.

“Anemia” refers to the condition of having less than the normal numberof red blood cells or less than the normal quantity of hemoglobin in theblood. The oxygen-carrying capacity of the blood is, therefore,decreased. Persons with anemia may feel tired and fatigue easily, appearpale, develop palpitations and become usually short of breath. Anemia iscaused by four basic factors: a) hemorrhage (bleeding); b) hemolysis(excessive destruction of red blood cells); c) underproduction of redblood cells; and d) not enough normal hemoglobin. There are many formsof anemia, including aplastic anemia, benzene poisoning, Fanconi anemia,hemolytic disease of the newborn, hereditary spherocytosis, irondeficiency anemia, osteopetrosis, pernicious anemia, sickle celldisease, thalassemia, myelodysplastic syndrome, and a variety of bonemarrow diseases. As contemplated herein, the SARM compounds of thepresent invention are useful in preventing and/or treating any one ormore of the above-listed forms of anemia.

“Obesity” refers to the state of being well above one's normal weight.Traditionally, a person is considered to be obese if they are more than20 percent over their ideal weight. Obesity has been more preciselydefined by the National Institute of Health (NIH) as a Body to MassIndex (BMI) of 30 or above. Obesity is often multifactorial, based onboth genetic and behavioral factors. Overweight due to obesity is asignificant contributor to health problems. It increases the risk ofdeveloping a number of diseases including: Type 2 (adult-onset)diabetes; high blood pressure (hypertension); stroke (cerebrovascularaccident or CVA); heart attack (myocardial infarction or MI); heartfailure (congestive heart failure); cancer (certain forms such as cancerof the prostate and cancer of the colon and rectum); gallstones andgallbladder disease (cholecystitis); Gout and gouty arthritis;osteoarthritis (degenerative arthritis) of the knees, hips, and thelower back; sleep apnea (failure to breath normally during sleep,lowering blood oxygen); and Pickwickian syndrome (obesity, red face,underventilation and drowsiness). As contemplated herein, the term“obesity” includes any one of the above-listed obesity-relatedconditions and diseases. Thus the SARM compounds of the presentinvention are useful in preventing and/or treating obesity and any oneor more of the above-listed obesity-related conditions and diseases.

“Prostate cancer” is one of the most frequently occurring cancers amongmen in the United States, with hundreds of thousands of new casesdiagnosed each year. Over sixty percent of newly diagnosed cases ofprostate cancer are found to be pathologically advanced, with no cureand a dismal prognosis. One third of all men over 50 years of age have alatent form of prostate cancer that may be activated into thelife-threatening clinical-prostate cancer form. The frequency of latentprostatic tumors has been shown to increase substantially with eachdecade of life from the 50s (5.3-14%) to the 90s (40-80%). The number ofpeople with latent prostate cancer is the same across all cultures,ethnic groups, and races, yet the frequency of clinically aggressivecancer is markedly different. This suggests that environmental factorsmay play a role in activating latent prostate cancer.

Pharmaceutical Compositions

The treatment methods of the present invention comprise, in oneembodiment, administering a pharmaceutical preparation comprising theSARM compound and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal or any combination thereof; and apharmaceutically acceptable carrier.

As used herein, “pharmaceutical composition” means a compositioncomprising an “effective amount” of the active ingredient, i.e. the SARMcompound, together with a pharmaceutically acceptable carrier ordiluent.

An “effective amount” as used herein refers to that amount whichprovides a therapeutic effect for a given condition and administrationregimen. An “effective amount” of the SARM compounds as used herein canbe in the range of 1-500 mg/day. In one embodiment the dosage is in therange of 1-100 mg/day. In another embodiment the dosage is in the rangeof 100-500 mg/day. In another embodiment the dosage is in a range of45-60 mg/day. In another embodiment the dosage is in the range of 15-25mg/day. In another embodiment the dosage is in the range of 55-65mg/day. In another embodiment the dosage is in the range of 45-60mg/day. The SARM compounds can be administered daily, in single dosageforms containing the entire amount of daily dose, or can be administereddaily in multiple doses such as twice daily or three times daily. TheSARM compounds can also be administered intermittently, for exampleevery other day, 3 days a week, four days a week, five days a week andthe like.

As used herein, the term “treating” includes preventative as well asdisorder remitative treatment. As used herein, the terms “reducing”,“suppressing” and “inhibiting” have their commonly understood meaning oflessening or decreasing. As used herein, the term “facilitating” isgiving its commonly understood meaning of increasing the rate. As usedherein, the term “promoting” is given its commonly understood meaning ofincreasing. As used herein, the term “progression” means increasing inscope or severity, advancing, growing or becoming worse.

As used herein, the term “administering” refers to bringing a subject incontact with a SARM compound of the present invention. As used herein,administration can be accomplished in vitro, i.e. in a test tube, or invivo, i.e. in cells or tissues of living organisms, for example humans.In one embodiment, the present invention encompasses administering thecompounds of the present invention to a subject. In one embodiment, thesubject is a mammalian subject. In another embodiment, the subject is ahuman.

The pharmaceutical compositions containing the SARM agent can beadministered to a subject by any method known to a person skilled in theart, such as parenterally, paracancerally, transmucosally,transdermally, intramuscularly, intravenously, intradermally,subcutaneously, intraperitonealy, intraventricularly, intracranially,intravaginally or intratumorally.

In one embodiment, the pharmaceutical compositions are administeredorally, and are thus formulated in a form suitable for oraladministration, i.e. as a solid or a liquid preparation. Suitable solidoral formulations include tablets, capsules, pills, granules, pelletsand the like. Suitable liquid oral formulations include solutions,suspensions, dispersions, emulsions, oils and the like. In oneembodiment of the present invention, the SARM compounds are formulatedin a capsule. In accordance with this embodiment, the compositions ofthe present invention comprise in addition to the SARM active compoundand the inert carrier or diluent, a hard gelating capsule.

Further, in another embodiment, the pharmaceutical compositions areadministered by intravenous, intraarterial, or intramuscular injectionof a liquid preparation. Suitable liquid formulations include solutions,suspensions, dispersions, emulsions, oils and the like. In oneembodiment, the pharmaceutical compositions are administeredintravenously, and are thus formulated in a form suitable forintravenous administration. In another embodiment, the pharmaceuticalcompositions are administered intraarterially, and are thus formulatedin a form suitable for intraarterial administration. In anotherembodiment, the pharmaceutical compositions are administeredintramuscularly, and are thus formulated in a form suitable forintramuscular administration.

Further, in another embodiment, the pharmaceutical compositions areadministered topically to body surfaces, and are thus formulated in aform suitable for topical administration. Suitable topical formulationsinclude gels, ointments, creams, lotions, drops and the like. Fortopical administration, the SARM agents or their physiologicallytolerated derivatives such as salts, esters, N-oxides, and the like areprepared and applied as solutions, suspensions, or emulsions in aphysiologically acceptable diluent with or without a pharmaceuticalcarrier.

Further, in another embodiment, the pharmaceutical compositions areadministered as a suppository, for example a rectal suppository or aurethral suppository. Further, in another embodiment, the pharmaceuticalcompositions are administered by subcutaneous implantation of a pellet.In a further embodiment, the pellet provides for controlled release ofSARM agent over a period of time.

In another embodiment, the active compound can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990); Treat et al., in Liposomes in the Therapy of Infectious Diseaseand Cancer, Lopez- Berestein and Fidler (eds.), Liss, New York, pp.353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid).

As used herein “pharmaceutically acceptable carriers or diluents” arewell known to those skilled in the art. The carrier or diluent may be asolid carrier or diluent for solid formulations, a liquid carrier ordiluent for liquid formulations, or mixtures thereof.

Solid carriers/diluents include, but are not limited to, a gum, a starch(e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.microcrystalline cellulose), an acrylate (e.g. polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

For liquid formulations, pharmaceutically acceptable carriers may beaqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, emulsions orsuspensions, including saline and buffered media. Examples of oils arethose of petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, andfish-liver oil.

Parenteral vehicles (for subcutaneous, intravenous, intraarterial, orintramuscular injection) include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's and fixedoils. Intravenous vehicles include fluid and nutrient replenishers,electrolyte replenishers such as those based on Ringer's dextrose, andthe like. Examples are sterile liquids such as water and oils, with orwithout the addition of a surfactant and other pharmaceuticallyacceptable adjuvants. In general, water, saline, aqueous dextrose andrelated sugar solutions, and glycols such as propylene glycols orpolyethylene glycol are preferred liquid carriers, particularly forinjectable solutions. Examples of oils are those of petroleum, animal,vegetable, or synthetic origin, for example, peanut oil, soybean oil,mineral oil, olive oil, sunflower oil, and fish-liver oil.

In addition, the compositions may further comprise binders (e.g. acacia,cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropylcellulose, hydroxypropyl methyl cellulose, povidone), disintegratingagents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide,croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate),buffers (e.g., Tris-HCl., acetate, phosphate) of various pH and ionicstrength, additives such as albumin or gelatin to prevent absorption tosurfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acidsalts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate),permeation enhancers, solubilizing agents (e.g., glycerol, polyethyleneglycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite,butylated hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose,hydroxypropylmethyl cellulose), viscosity increasing agents (e.g.carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum),sweetners (e.g. aspartame, citric acid), preservatives (e.g.,Thimerosal, benzyl alcohol, parabens), lubricants (e.g. stearic acid,magnesium stearate, polyethylene glycol, sodium lauryl sulfate),flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethylphthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropylcellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers orpoloxamines), coating and film forming agents (e.g. ethyl cellulose,acrylates, polymethacrylates) and/or adjuvants.

In one embodiment, the pharmaceutical compositions provided herein arecontrolled release compositions, i.e. compositions in which the SARMcompound is released over a period of time after administration.Controlled or sustained release compositions include formulation inlipophilic depots (e.g. fatty acids, waxes, oils). In anotherembodiment, the composition is an immediate release composition, i.e. acomposition in which all of the SARM compound is released immediatelyafter administration.

In yet another embodiment, the pharmaceutical composition can bedelivered in a controlled release system. For example, the agent may beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit.Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980);Saudek et al., N. Engl. J. Med. 321:574 (1989). In another embodiment,polymeric materials can be used. In yet another embodiment, a controlledrelease system can be placed in proximity to the therapeutic target,i.e., the brain, thus requiring only a fraction of the systemic dose(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 115-138 (1984). Other controlled release systems arediscussed in the review by Langer (Science 249:1527-1533 (1990).

The compositions may also include incorporation of the active materialinto or onto particulate preparations of polymeric compounds such aspolylactic acid, polyglycolic acid, hydrogels, etc, or onto liposomes,microemulsions, micelles, unilamellar or multilamellar vesicles,erythrocyte ghosts, or spheroplasts.) Such compositions will influencethe physical state, solubility, stability, rate of in vivo release, andrate of in vivo clearance.

Also comprehended by the invention are particulate compositions coatedwith polymers (e.g. poloxamers or poloxamines) and the compound coupledto antibodies directed against tissue-specific receptors, ligands orantigens or coupled to ligands of tissue-specific receptors.

Also comprehended by the invention are compounds modified by thecovalent attachment of water-soluble polymers such as polyethyleneglycol, copolymers of polyethylene glycol and polypropylene glycol,carboxymethyl cellulose, dextran, polyvinyl alcohol,polyvinylpyrrolidone or polyproline. The modified compounds are known toexhibit substantially longer half-lives in blood following intravenousinjection than do the corresponding unmodified compounds (Abuchowski etal., 1981; Newmark et al., 1982; and Katre et al., 1987). Suchmodifications may also increase the compound's solubility in aqueoussolution, eliminate aggregation, enhance the physical and chemicalstability of the compound, and greatly reduce the immunogenicity andreactivity of the compound. As a result, the desired in vivo biologicalactivity may be achieved by the administration of such polymer-compoundabducts less frequently or in lower doses than with the unmodifiedcompound.

The preparation of pharmaceutical compositions which contain an activecomponent is well understood in the art, for example by mixing,granulating, or tablet-forming processes. The active therapeuticingredient is often mixed with excipients which are pharmaceuticallyacceptable and compatible with the active ingredient. For oraladministration, the SARM agents or their physiologically toleratedderivatives such as salts, esters, N-oxides, and the like are mixed withadditives customary for this purpose, such as vehicles, stabilizers, orinert diluents, and converted by customary methods into suitable formsfor administration, such as tablets, coated tablets, hard or softgelatin capsules, aqueous, alcoholic or oily solutions. For parenteraladministration, the SARM agents or their physiologically toleratedderivatives such as salts, esters, N-oxides, and the like are convertedinto a solution, suspension, or emulsion, if desired with the substancescustomary and suitable for this purpose, for example, solubilizers orother.

An active component can be formulated into the composition asneutralized pharmaceutically acceptable salt forms. Pharmaceuticallyacceptable salts include the acid addition salts (formed with the freeamino groups of the polypeptide or antibody molecule), which are formedwith inorganic acids such as, for example, hydrochloric or phosphoricacids, or such organic acids as acetic, oxalic, tartaric, mandelic, andthe like. Salts formed from the free carboxyl groups can also be derivedfrom inorganic bases such as, for example, sodium, potassium, ammonium,calcium, or ferric hydroxides, and such organic bases as isopropylamine,trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

For use in medicine, the salts of the SARM will be pharmaceuticallyacceptable salts. Other salts may, however, be useful in the preparationof the compounds according to the invention or of their pharmaceuticallyacceptable salts. Suitable pharmaceutically acceptable salts of thecompounds of this invention include acid addition salts which may, forexample, be formed by mixing a solution of the compound according to theinvention with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid,maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid,citric acid, tartaric acid, carbonic acid or phosphoric acid.

In one embodiment, the methods of the present invention compriseadministering a SARM compound as the sole active ingredient. However,also encompassed within the scope of the present invention are methodsof a) male contraception; b) treatment of a variety of hormone-relatedconditions, for example conditions associated with Androgen Decline inAging Male (ADAM); c) treatment of conditions associated with AndrogenDecline in Female (ADIF); d) treatment and/or prevention of acute and/orchronic muscular wasting conditions; e) preventing and/or treating dryeye conditions; f) oral androgen replacement therapy; g) decreasing theincidence of, halting or causing a regression of prostate cancer; and h)inducing apoptosis in a cancer cell as disclosed herein, which compriseadministering the SARM compounds in combination with one or moretherapeutic agents. These agents include, but are not limited to: LHRHanalogs, reversible antiandrogens, antiestrogens, anticancer drugs,5-alpha reductase inhibitors, aromatase inhibitors, progestins, oragents acting through other nuclear hormone receptors.

Thus, in one embodiment, the present invention provides compositions andpharmaceutical compositions comprising a selective androgen receptormodulator compound, in combination with an LHRH analog. In anotherembodiment, the present invention provides compositions andpharmaceutical compositions comprising a selective androgen receptormodulator compound, in combination with a reversible antiandrogen. Inanother embodiment, the present invention provides compositions andpharmaceutical compositions comprising a selective androgen receptormodulator compound, in combination with an antiestrogen. In anotherembodiment, the present invention provides compositions andpharmaceutical compositions comprising a selective androgen receptormodulator compound, in combination with an anticancer drug. In anotherembodiment, the present invention provides compositions andpharmaceutical compositions comprising a selective androgen receptormodulator compound, in combination with a 5-alpha reductase inhibitor.In another embodiment, the present invention provides compositions andpharmaceutical compositions comprising a selective androgen receptormodulator compound, in combination with an aromatase inhibitor. Inanother embodiment, the present invention provides compositions andpharmaceutical compositions comprising a selective androgen receptormodulator compound, in combination with a progestin. In anotherembodiment, the present invention provides compositions andpharmaceutical compositions comprising a selective androgen receptormodulator compound, in combination with an agent acting through othernuclear hormone receptors.

It will be appreciated by a person skilled in the art that the presentinvention is not limited by what has been particularly shown anddescribed hereinabove. Rather, the scope of the invention is defined bythe claims that follow:

1. A selective androgen receptor modulator (SARM) compound representedby the structure of formula I:

wherein G is O or S; X is a bond or CH₂; T is OH, OR, —NHCOCH₃, orNHCOR; Z is NO₂, CN, COOH, COR, NHCOR or CONHR; Y is CF₃, F, T, Br, Cl,CN, C(R)₃ or Sn(R)₃; Q together with the benzene ring to which it isattached is a fused ring system represented by structure A, B or C:

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and R₁ is CH₃, CH₂F,CHF₂, CF₃, CH₂CH₃ or CF₂CF₃; or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, or any combinationthereof.
 2. The selective androgen receptor modulator compound of claim1, wherein X is a bond.
 3. The selective androgen receptor modulatorcompound of claim 1, wherein X is CH₂.
 4. The selective androgenreceptor modulator compound of claim 1, wherein G is O.
 5. The selectiveandrogen receptor modulator compound of claim 1, wherein Z is NO₂. 6.The selective androgen receptor modulator compound of claim 1, wherein Zis CN.
 7. The selective androgen receptor modulator compound of claim 1,wherein Y is CF₃.
 8. The selective androgen receptor modulator compoundof claim 1, wherein T is OH.
 9. The selective androgen receptormodulator compound of claim 1, wherein R₁ is CH₃.
 10. The selectiveandrogen receptor modulator compound of claim 1, wherein Z is in thepara position.
 11. The selective androgen receptor modulator compound ofclaim 1, wherein Y is in the meta position.
 12. The selective androgenreceptor modulator compound of claim 1, represented by the structure offormula IIa.


13. The selective androgen receptor modulator compound of claim 1,represented by the structure of formula IIb.


14. The selective androgen receptor modulator compound of claim 1,wherein said compound is an androgen receptor agonist.
 15. A compositioncomprising the selective androgen receptor modulator compound of claim 1and/or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, or any combination thereof; and a suitablecarrier or diluent.
 16. A pharmaceutical composition comprising aneffective amount of the selective androgen receptor modulator compoundof claim 1 and/or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, or any combination thereof;and a pharmaceutically acceptable carrier or diluent.
 17. A method ofbinding a selective androgen receptor modulator compound to an androgenreceptor, comprising the step of contacting the androgen receptor withthe selective androgen receptor modulator compound of claim 1 and/or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, or any combination thereof, in an amount effective tobind the selective androgen receptor modulator compound to the androgenreceptor.
 18. A selective androgen receptor modulator (SARM) compoundrepresented by the structure of formula V:

wherein X is a bond or CH₂; Z is NO₂, CN, COOH, COR, NHCOR or CONHR; Yis CF₃, F, I, Br, Cl, CN, C(R)₃ or Sn(R)₃; Q together with the benzenering to which it is attached is a fused ring system represented bystructure A, B or C:

and R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; or its isomer,metabolite, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, or any combination thereof.
 19. The selective androgenreceptor modulator compound of claim 18, wherein X is a bond.
 20. Theselective androgen receptor modulator compound of claim 18, wherein Z isNO₂.
 21. The selective androgen receptor modulator compound of claim 18,wherein Z is CN.
 22. The selective androgen receptor modulator compoundof claim 18, wherein Y is CF₃.
 23. The selective androgen receptormodulator compound of claim 18, represented by the structure of formulaVIa:


24. The selective androgen receptor modulator compound of claim 18,represented by the structure of formula VIb.


25. The selective androgen receptor modulator compound of claim 18,wherein said compound is an androgen receptor agonist.
 26. A compositioncomprising the selective androgen receptor modulator compound of claim18 or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, or any combination thereof; and a suitablecarrier or diluent.
 27. A pharmaceutical composition comprising aneffective amount of the selective androgen receptor modulator compoundof claim 18 or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, or any combination thereof;and a pharmaceutically acceptable carrier or diluent.
 28. A method ofbinding a selective androgen receptor modulator compound to an androgenreceptor, comprising the step of contacting the androgen receptor withthe selective androgen receptor modulator compound of claim 18 or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, or any combination thereof, in an amount effective tobind the selective androgen receptor modulator compound to the androgenreceptor.
 29. A method of suppressing spermatogenesis in a subjectcomprising contacting an androgen receptor of the subject with theselective androgen receptor modulator compound of formula I:

wherein G is O or S; X is a bond or CH₂; T is OH, OR, —NHCOCH₃, orNHCOR; Z is NO₂, CN, COOH, COR, NHCOR or CONHR; Y is CF₃, F, I, Br, Cl,CN, C(R)₃ or Sn(R)₃; Q is alkyl, F, Cl, Br, I, CF₃, CN, C(R)₃, Sn(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR, NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R or SR; or Qtogether with the benzene ring to which it is attached is a fused ringsystem represented by structure A, B or C:

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH; and R₁ is CH₃, CH₂F,CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, or any combinationthereof, in an amount effective to suppress sperm production.
 30. Amethod of contraception in a male subject, comprising the step ofadministering to said subject the selective androgen receptor modulatorcompound of claim
 1. 31. A method of hormone therapy comprising the stepof contacting an androgen receptor of a subject with the selectiveandrogen receptor modulator compound of claim
 1. 32. A method of hormonereplacement therapy comprising the step of contacting an androgenreceptor of a subject with the selective androgen receptor modulatorcompound of claim
 1. 33. A method of treating a subject having a hormonerelated condition, comprising the step of administering to said subjectthe selective androgen receptor modulator compound of claim
 1. 34. Amethod of treating a subject suffering from prostate cancer, comprisingthe step of administering to said subject the selective androgenreceptor modulator compound of claim
 1. 35. A method of preventingprostate cancer in a subject, comprising the step of administering tosaid subject the selective androgen receptor modulator compound ofclaim
 1. 36. A method of delaying the progression of prostate cancer ina subject suffering from prostate cancer, comprising the step ofadministering to said subject the selective androgen receptor modulatorcompound of claim
 1. 37. A method of preventing the recurrence ofprostate cancer in a subject suffering from prostate cancer, comprisingthe step of administering to said subject the selective androgenreceptor modulator compound of claim
 1. 38. A method of treating therecurrence of prostate cancer in a subject suffering from prostatecancer, comprising the step of administering to said subject theselective androgen receptor modulator compound of claim
 1. 39. A methodof treating a dry eye condition in a subject suffering from dry eyes,comprising the step of administering to said subject the selectiveandrogen receptor modulator compound of claim
 1. 40. A method ofpreventing a dry eye condition in a subject, comprising the step ofadministering to said subject the selective androgen receptor modulatorcompound of claim
 1. 41. A method of inducing apoptosis in a cancercell, comprising the step of contacting said cell with the selectiveandrogen receptor modulator compound of claim 1.